This project is based on a recent observation that osteoblasts are a regulatory component of the hematopoietic stem cell niche and can be targeted as a means to increase stem cell numbers. Activation of the parathyroid hormone (PTH)/parathyroid related hormone receptor (PPR) resulted in Notch pathway activation and thereby expansion of hematopoietic stem cells in a mouse model. This was accompanied by a marked improvement in animal survival following bone marrow transplantation with limiting numbers of hematopoietic stem cells. This project will assess the potential for extending this model to a clinical context by pursuing the following specific aims: Aim 1: Define whether stimulation of the stem cell niche with PTH can result in improved donor stem cell harvests. Aim 2: Determine if manipulation of the graft or niche can affect the kinetics of immune recovery. Aim 3: Determine if ex vivo manipulation of the graft and the niche can synergistically increase stem cell engraftment efficiency. Accomplishment of these aims depends upon the clinical and large animal components of this Program Project and would not be achievable without the PO1 mechanism. Successful completion of this project will provide critical information about the value of using PTH specifically and targeting the stem cell niche more generally in stem cell based therapies for human disease.